Precision oncology requires delivering the right drug to the right patient at the right time, but ?time? is rarely studied preclinically before a new drug enters the clinic. As a result, drugs shown to prevent progression of advanced/metastatic solid tumors are sometimes found to be ineffective at preventing recurrence when administered in the adjuvant or neoadjuvant settings. The long-term clinical benefit realized from adjuvant and neoadjuvant therapies lies in anti-cancer effects on residual/disseminated/micrometastatic, clinically dormant cancer cells that are undetectable by routine clinical methods; the biology underlying such anti-cancer effects is practically unknown, creating a gap for evaluating new drugs. Clinically dormant cancer cells that survive (neo)adjuvant therapy can ultimately give rise to recurrent/advanced tumors that frequently develop resistance to all approved therapies. Thus, understanding how clinically dormant cancer cells vs. established tumors respond to a novel therapy will guide clinical testing in the appropriate disease setting(s), and reveal targets for combination therapies to enhance efficacy. More thorough characterization of drug efficacy in relevant preclinical models will increase the drug success rate in clinical trials, thus decreasing the cost of drug development. Estrogen receptor ? (ER)-positive breast cancer is a disease for which improved drug development could ultimately impact treatment options for hundreds of thousands of patients. Patients with early-stage ER+ breast cancer are treated with adjuvant anti-estrogen therapies that neutralize ER and suppress, but do not eliminate, tumor-initiating cells. We and others have implicated activation of the phosphatidylinositol 3-kinase (PI3K) pathway in anti-estrogen resistance, and PI3K inhibitors (PI3Ki) are in clinical development in combination with anti-estrogens. Based on our preliminary findings, we hypothesize that short-term treatment with anti-estrogen/PI3Ki combination therapy kills clinically dormant ER+ breast cancer cells and prevents recurrence (Aim 2), while established tumors develop resistance to anti- estrogen/PI3Ki therapy via suppression of apoptosis (Aim 1) due in part to microenvironmental cytokine signaling (Aim 3). We will test this hypothesis through the following Specific Aims: 1) To determine why anti- estrogen/PI3Ki combination therapy is acutely but not sustainably cytotoxic in established ER+ breast tumors; 2) To determine how clinically dormant ER+ breast tumor cells respond to short-term anti-estrogen/PI3Ki combination therapy; 3) To identify cytokines in stroma-derived secretomes that drive resistance to anti- estrogen and anti-estrogen/PI3Ki therapies in ER+ breast cancer. These studies are aligned with the NCI Precision Medicine Initiative of Overcoming Drug Resistance, the Cancer Moonshot Panel recommendation to develop ways to overcome cancer's resistance to therapy, and the NCI Provocative Question `What cancer models or other approaches can be developed to study clinically stable disease and the subsequent transition to progressive disease?'